Purpose

The purpose of this study is to test the effects of a drug called Voraxaze when it's routinely given in combination with methotrexate and rituximab, the standard treatment for CNSL.

Condition

Eligibility

Eligible Ages
Over 18 Years
Eligible Genders
All
Accepts Healthy Volunteers
No

Inclusion Criteria

Arm A:

- Histologically documented B-cell non-Hodgkin‟s lymphoma involving the brain, spinal cord, and/or leptomeningeal space.

°Patients in whom the type of lymphoma could not be determined or is unknown (e.g., not enough tissue for further analysis) are assumed to have a B cell lymphoma and are eligible

- Patients with parenchymal lesions must have received no more than two cycles of treatment for treatment of CNS lymphoma or have unequivocal evidence of disease progression on imaging (MRI of the brain/spine or CT head) 28 days prior to study registration. For patients with leptomeningeal disease only, CSF cytology must document lymphoma cells and/or imaging findings must be consistent with CSF disease 28 days prior to study registration (at the discretion of the investigator).

- Patients who have already received two doses of treatment of CNS lymphoma are eligible for enrollment.

- (Arm A only) as long as they are planned for at least 6 additional doses of methotrexate. Patients must not have evidence of systemic non-Hodgkin lymphoma requiring active treatment.

- Men and woman must be at least 18 years of age on the day of consenting to the study.

- Patients must have a Karnofsky Performance Status (KPS) ≥ 50 (See Appendix 2).

- Patients must be willing and able to comply with scheduled visits, treatment plan, and laboratory tests.

- Patients must have adequate bone marrow and organ function shown by:

- Absolute neutrophil count (ANC) ≥ 1.0 x 10^9/L;

- Platelets ≥ 100 x 10^9/L and no platelet transfusion within the past 28 days prior to study registration;

- Hemoglobin (Hgb) ≥ 8 g/dL and no red blood cells (RBC) transfusion within the past 28 days prior to study registration;

- International Normalized Ratio (INR) ≤ 1.5 and PTT (aPTT) ≤ 1.5 times the upper limit of normal;

- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 times the upper limit of normal;

- Serum bilirubin ≤ 1.5 times the upper limit of normal; or total bilirubin ≤ 3 times the upper limit of normal with direct bilirubin within the normal range in patients with well documented Gilbert Syndrome;

- CrCl ≥ 60 mL/min using the Cockcroft-Gault equation. Men: CrCl (min/mL) = (140-age) X (actual weight in kg) / 72 X serum creatinine (mg/dL) Women: CrCl (mL/min) = (140-age) X (actual weight in kg) X 0.85 / 72 X serum creatinine (mg/dL)

- Women of reproductive potential must agree to use highly effective methods of birth control during the period of therapy and for 30 days after the last dose of the study drug. Men who are sexually active must agree to use highly effective contraception during the period of therapy and for 3 months after the last dose.

- Female subjects of childbearing potential must have a negative plasma pregnancy test upon study entry.

- Patients must be able to tolerate MRI/CT scans.

- Patients must be able to tolerate lumbar puncture and/or Ommaya taps.

- Participants must have recovered to grade 1 toxicity from prior therapy. NOTE: Patients who have initiated and received up to two cycles of treatment will NOT be excluded from study Arm A as long as all pretreatment assessments have been completed within 28 days of trial initiation.

Arm B:

- Histologically documented B-cell non-Hodgkin's lymphoma involving the brain, spinal cord, and/or leptomeningeal space

° Patients in whom the type of lymphoma could not be determined or is unknown (e.g., not enough tissue for further analysis) are assumed to have a B cell lymphoma and are eligible

- Patients must be treatment naïve or have unequivocal evidence of disease progression on imaging (MRI of the brain/spine or CT head) 28 days prior to study registration. For patients with leptomeningeal disease only, CSF cytology must document lymphoma cells and/or imaging findings must be consistent with CSF disease 28 days prior to study registration (at the discretion of the investigator)

- Patients must not have evidence of systemic non-Hodgkin lymphoma requiring active treatment

- Men and woman must be at least 18 years of age on the day of consenting to the study

- Patients must have a Karnofsky Performance Status (KPS) >/= 70 or >/= 50 if KPS is due to a neurologic deficit attributed to active disease

- Patients must be willing and able to comply with scheduled visits, treatment plan, and laboratory tests

- Patients must have adequate bone marrow and organ function shown by:

- Absolute neutrophil count (ANC) >/= 1.0 x 10^9/L

- Platelets >/= 100 x 10^9/L and no platelet transfusion within the past 28 days prior to study registration

- Hemoglobin (Hgb) >/= 8g/dL and no red blood cells (RBC) transfusion within the past 28 days prior to study registration

- International Normalized Ratio (INR) </= 1.5 and PTT (aPTT) </= 1.5 times the upper limit of normal

- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) </= 3 times the upper limit of normal

- Serum bilirubin </= 1.5 times the upper limit of normal; or total bilirubin </= 3 times the upper limit of normal with direct bilirubin within the normal range in patients with well documented Gilbert Syndrome

- CrCl >/= 60 mL/min using the Cockcroft-Gault equation Men: CrCl (min/mL) = (140-age) X (actual weight in kg) / 72 X serum creatinine (mg/dL) Women: CrCl (mL/min) = (140-age) X (actual weight in kg) X 0.85 / 72 X serum creatinine (mg/dL)

- Women of reproductive potential must agree to use highly effective methods of birth control during the period of therapy and for 30 days after the last dose of the study drug. Men who are sexually active must agree to use highly effective contraception during the period of therapy and for 3 months after the last dose.

- Female subjects of childbearing potential must have a negative plasma pregnancy test upon study entry

- Patients must be able to tolerate MRI/CT scans

- Patients must be able to tolerate lumbar puncture and/or Ommaya taps

- Participants must have recovered to grade 1 toxicity from prior therapy

NOTE: Prior autologous stem cell transplant as well as prior radiation to the CNS does NOT prevent patients from enrollment into the trial.

Exclusion Criteria

Arms A and B:

- Patient with SCNSL requiring treatment for extra-CNS disease are excluded.

- Patient concurrently using other approved or investigational antineoplastic agents.

- Patient has received chemotherapy, monoclonal antibodies or targeted anticancer therapy ≤ 4 weeks or 5 half-lives, whichever is shorter, or 6 weeks for nitrosoureas or mitomycin-C prior to starting the study drug, or the patient has not recovered from the side effects of such therapy. Exceptions are allowed for rituximab and methotrexate for patients enrolling Arm A as long as patients have recovered from side effects.

- Patient has received external beam radiation therapy to the CNS within 28 days of the first dose of the study drug.

- Patient has an active concurrent malignancy requiring active therapy.

- The patient has been treated with radio- or toxin-immunoconjugates within 70 days of the first dose of the study drug.

- Patient weighs <40kg

- Patient is allergic to components of the study drug.

- Patient is known to have human immunodeficiency virus (HIV) infection.

- Patient is known to have a history of active or chronic infection with hepatitis C virus (HCV) or hepatitis B virus (HBV) as determined by serologic tests.

- Severe, active medical co-morbidity such as unstable angina and/or congestive heart failure, coronary artery disease, significant abnormalities on electrocardiogram (EKG), uncontrolled or symptomatic arrhythmias or valvular disease; active infection, severe chronic obstructive pulmonary disease or other respiratory illness, hepatic insufficiency, known pre-existing immunodeficiency as seen in organ transplant recipients, renal failure with CrCl <60 mL/min.

- Patient has a life-threatening illness, medical condition, or organ system dysfunction that, in the opinion of the investigator, could compromise the subject‟s safety or put the study outcomes at undue risk.

- Patient has large pleural or ascetic fluid collection.

- Pregnancy or women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception; this exclusion is necessary because the treatment involved in this study may be significantly teratogenic.

- Prior severe allergic reaction to any of the study drugs that cannot be resolved with medication.

- Patient has undergone prior allogenic stem cell transplant (autologous stem cell transplant is NOT an exclusion).

Study Design

Phase
Early Phase 1
Study Type
Interventional
Allocation
Non-Randomized
Intervention Model
Parallel Assignment
Intervention Model Description
This is an open-label, non-randomized, pilot study of Voraxaze administered following standard of care MTX and rituximab in patients with CNS lymphoma.
Primary Purpose
Treatment
Masking
None (Open Label)

Arm Groups

ArmDescriptionAssigned Intervention
Experimental
MTX 3 g/m^2
Patients will receive rituximab Day 1 (+/- 7 days) and MTX Day 2 (+/- 7 days) as per standard of care. Voraxaze will be administered each cycle 24 hours (+/- 2 h) after start of MTX infusion. Dose of Voraxaze will be 2000 units during cycles 1-4, and 1000 units during cycles 5-8. Patients will be treated with rituximab 500 mg/m^2. (Cohort A) will receive MTX 3 g/m2. Patients will also receive standard of care leucovorin rescue starting at least 24 hours after MTX and 2 hours after Voraxaze. Cycles will be 14 days long.
  • Drug: Voraxaze
    Dose of Voraxaze will be 2000 units during cycles 1-4, and 1000 units during cycles 5-8.
  • Drug: Methotrexate
    (Cohort A) will receive MTX 3 g/m2 or (Cohort B) will receive MTX 8 g/m^2
  • Drug: Rituximab
    Patients will be treated with rituximab 500 mg/m^2.
  • Drug: leucovorin
    Patients will also receive standard of care leucovorin rescue starting at least 24 hours after MTX and 2 hours after Voraxaze. Cycles will be 14 days long.
Experimental
MTX 8 g/m^2
Patients will receive up to 8 cycles of treatment consisting of rituximab Day 1 (+/- 7 days) and MTX Day 2 (+/- 7 days) as per standard of care. Voraxaze will be administered each cycle 24 hours (+/- 2 h) after start of MTX infusion. Dose of Voraxaze will be 2000 units during cycles 1-4, and 1000 units during cycles 5-8. Patients will be treated with rituximab 500 mg/m^2. (Cohort B) will receive MTX 8 g/m2. Patients will also receive standard of care leucovorin rescue starting at least 24 hours after MTX and 2 hours after Voraxaze. Cycles will be 14 days long.
  • Drug: Voraxaze
    Dose of Voraxaze will be 2000 units during cycles 1-4, and 1000 units during cycles 5-8.
  • Drug: Methotrexate
    (Cohort A) will receive MTX 3 g/m2 or (Cohort B) will receive MTX 8 g/m^2
  • Drug: Rituximab
    Patients will be treated with rituximab 500 mg/m^2.
  • Drug: leucovorin
    Patients will also receive standard of care leucovorin rescue starting at least 24 hours after MTX and 2 hours after Voraxaze. Cycles will be 14 days long.

Recruiting Locations

University of Alabama at Birmingham
Birmingham, Alabama 35294
Contact:
Burt Nabors, MD
205-934-1432

More Details

Status
Recruiting
Sponsor
Memorial Sloan Kettering Cancer Center

Study Contact

Lauren Schaff, MD
212-610-0485
schaffl@mskcc.org

Notice

Study information shown on this site is derived from ClinicalTrials.gov (a public registry operated by the National Institutes of Health). The listing of studies provided is not certain to be all studies for which you might be eligible. Furthermore, study eligibility requirements can be difficult to understand and may change over time, so it is wise to speak with your medical care provider and individual research study teams when making decisions related to participation.